Cutis Bufonis extract gel skeleton slow releasing tablet and preparation method
Technical field
The present invention relates to a kind of gel skeleton type slow releasing tablet of Chinese medicine Cutis Bufonis, specifically the preparation of Cutis Bufonis extract gel skeleton type slow releasing tablet and in the application of clinicing aspect.
Background technology
Bufo siccus (toad) also cries Oviductus Ranae.Amphibian, body surface have many pimples, in poison gland is arranged, be commonly called as toad, leprosy thorn.Being divided into two kinds of Bufo siccus and Bufo melanostictus in China, is a kind of tcm clinical practice medicinal former animal commonly used.Just on the books in the Ancient books such as Shennong's Herbal, " China's book on Chinese herbal medicine ", " Mingyi Bielu ".Bufo siccus " acrid in the mouth, cool in nature, poisonous.GUIXIN, liver, spleen, lung meridian ", can " detoxicating and resolving stagnation of pathogens, removing food stagnancy diuretic, destroying parasites for curing malnutrition.Cure mainly carbuncle, furuncle, carbuncle on the back, scrofula, the malignant boil , mass in the abdomen hypochondriac lump, tympanites, edema, infantile malnutrition, tetanus, chronic cough and asthma ".The Chinese crude drug dry maxima skin is to remove the Bufo siccus of drying or drying behind the internal organs, and the structures such as bone, muscle are arranged.And Cutis Bufonis is after Bufonidae animal Bufo siccus Bufo bufo gargarizans Cantor or Bufo melanostictus Bufo melanostictus Schneider are taked Venenum Bufonis, the execution of choping off the head catches neck shoulder place skin to pull backward the bag-shaped skin with extremity that stripping obtains.Skin depth 0.2~0.3mm only is shrinkage Gou contraction shape after drying or drying, and extremity stretch or distortion, outer surface smoother, and inner surface has numerous miliaria scrofulas not of uniform size.Quality is firmly and extremely tough and tensile, and the dermatomere shape is difficult for bending, and difficulty fractures.Section is smooth, and fracture has fiber to link to each other.Sun Simiao claims: " it is swollen except disliking that toad is sloughed off (clothing), and god also." the Li Shizhen (1518-1593 A.D.) Compendium of Material Medica claims: " the toad clothing is that it holds sufficient the essence of five ZANG-organs and six FU-organs gas, receives the China of world negative and positive precious, if one of obtain, all foul diseases do not have and do not heal.”
The method of extracting at present effective ingredient in the Cutis Bufonis roughly has two kinds: a kind of is the method that adopts water extract-alcohol precipitation, and water soluble ingredient is more in the products therefrom, contains the bufogenin constituents of trace.Relevant report has: " cinobufacin (Cutis Bufonis) extract production process " (number of patent application 200510005277.4) is the preparation method of extract in the HUACHANSU ZHUSHEYE of Anhui Jinchan Biochemical Co., Ltd. development, oral liquid, the tablet.Another kind is to adopt organic solvent extraction, and extract separates through chromatographic column, organic solvent gradient elution in varing proportions.Relevant report has: " preparation of three kinds of anticancer compounds and preparation method thereof in Bufo siccus or the Venenum Bufonis " (number of patent application 200610045893.7), the total content of resibufogenin, cinobufacin and three kinds of compositions of Toadpoison Medicine 〉=80% in the extraction product; " a kind of Venenum Bufonis extract and preparation method thereof " (number of patent application 200710041880.7), the percentage by weight of the above-mentioned three kinds of products of gained 〉=90%; " toad skin total alkaloid and preparation thereof and analytical method with and preparation " (number of patent application 200710020339.8), wherein the indoles total alkaloid content is 50%~95%, the total amount of cinobufagin and resibufogenin is 0.02~0.08%, and the peaceful content of Bufo siccus thiophene is 20%~50%.Fat-soluble active constituent content is higher in this kind method extract, but complex process, complex operation, and cost is higher; By contrast, the first method simple possible, cost is low, and the content of effective ingredient is enough to meet clinical needs in the extraction product, easily promotes and adopts.
Modern pharmacology studies show that Cutis Bufonis extract has the effects such as heart tonifying, antitumor, local anaesthesia, analgesia, antiinflammatory.Be usually used in clinically in the treatment, the diseases such as late tumor and chronic hepatitis B.Common formulations has conventional tablet, oral liquid, capsule and injection etc. at present.But all there is drawback to a certain degree in these dosage forms, take medicine 3~4 times each 3~4 every day such as conventional tablet, medicining times is many, and dosage is large, and tumor and chronic hepatitis B patient all need this medicine of long-term taking, there is very large inconvenience, causes patient's medication poor compliance.Therefore, be necessary to study a kind of novel form, improve to a certain extent the deficiency that existing dosage form exists.
Oral sustained-release preparation can reduce medicining times because of it, reduces blood concentration fluctuation, and medicament curative effect enhancement reduces the focus of paying close attention to for people that forms of untoward reaction.Matrix tablet is because of its low production cost, and technique is simple, becomes one of the most frequently used oral sustained-release preparation.Hydrogel matrix tablet is a kind of in the matrix sustained release tablet, and the production development cycle is short, easily drops into suitability for industrialized production, has very strong practicality, occupies 60~70% of listing matrix tablet.Hydrogel matrix tablet (Hydrophilic Matrix Tablet) is the tablet of making as framework material take hydrophilic polymer or natural gum class.Can meet by framework material the gel barrier control drug release of water or Digestive system formation.
Because method of granulating commonly used is with mixing of materials all in the sustained-release tablet recipe at present, add an amount of wetting agent or binding agent and granulate, the Chinese medicine sustained release tablets of preparation drug release rate in early stage is slower like this, later stage release quantity not sufficient.In use produce effects is slow, wants to obtain effectively to treat concentration and takes longlyer, can not reach the requirement of desirable slow releasing preparation.
Existing studies show that can be improved the rate of release of slow releasing preparation Chinese medicine by adding porogen, increase total release percentage.Principle is that porogen is met water or Digestive system dissolves, in the gel layer barrier, form complicated duct, destroyed the seriality of gel, make water or Digestive system can penetrate in the matrix tablet, accelerate dissolving and the diffusion of medicine, improve aquation and the corrosion speed of framework material.Generally, porogen is less on the release impact in medicine early stage, and is larger on later stage release impact.Reason is, in the starting stage of drug release, discharges mainly take concentration difference as motive force; And when drug release to a certain extent, the inside and outside concentration difference of medicine hour, the principal element that affect release is then changed into the framing structure of medicine itself by concentration difference, namely the release duct how much.At this moment, the effect of porogen manifests, and slow releasing preparation later stage burst size increases.The slow releasing preparation release that obtains desirable.
Summary of the invention
The object of the invention is to overcome the deficiencies in the prior art, provide a kind of release to stablize lasting Cutis Bufonis extract gel skeleton slow releasing tablet.
Second purpose of the present invention is to provide the preparation method of Cutis Bufonis extract gel skeleton slow releasing tablet.
Technical scheme of the present invention is summarized as follows:
The preparation method of Cutis Bufonis extract gel skeleton slow releasing tablet, comprise the steps: to take by weighing the porogen of Cutis Bufonis extract extractum powder, framework material, filler and double taste masking, cross respectively 60 mesh sieves, described Cutis Bufonis extract extractum powder is divided into A part and B part, spray into an amount of ethanol or ethanol water wet granulation, drying behind A part and the described framework material mixing; Spray into an amount of ethanol or ethanol water wet granulation behind the porogen mixing of B part and filler and double taste masking, drying; Add the moderate lubrication agent after two parts of granules being mixed, tabletting namely obtains Cutis Bufonis extract gel skeleton slow releasing tablet again.
The mass percent of the porogen of described Cutis Bufonis extract extractum powder, framework material, filler and double taste masking is respectively: 30%~60%, 10%~35%:0%~48%:0%~30%, the mass ratio of described A part Cutis Bufonis extract extractum powder and B part Cutis Bufonis extract extractum powder is 1: 0.5-3.
Described Cutis Bufonis extract extractum powder is to make with following method: it is raw material that dry maxima skin is cleaned post-drying, soak 20-40min, decoct 2-4 time, each 30-60min that decocts, the quality that at every turn adds water is 8-12 times of described raw materials quality, filter, merging filtrate is concentrated into the 1/5-1/6 of original volume, add volumetric concentration and be 90% ethanol water and make that to contain amount of alcohol be 60%, 4 ℃ leave standstill 20-28h, filter, and filtrate is revolved and steamed to nothing alcohol flavor, add volumetric concentration and be 90% ethanol water and make that to contain amount of alcohol be 85%, 4 ℃ leave standstill 44-52h, filter, and filtrate revolving steamed to the thickness paste; 60 ℃ are dried to constant weight, pulverize.
Described framework material is hypromellose, ethyl cellulose or carbomer.
Described filler is microcrystalline Cellulose, lactose or starch.
The porogen of described double taste masking is mannitol, sorbitol or glucose.
Described lubricant is Pulvis Talci, micropowder silica gel or magnesium stearate.
The concentration of described ethanol water is 60%~100%.
The Cutis Bufonis extract gel skeleton slow releasing tablet of said method preparation.
Described tablet hardness is 4~7kg/cm
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Cutis Bufonis extract gel skeleton slow releasing tablet of the present invention is identical with Cutis Bufonis extract conventional tablet clinical application, all is in the treatment, the diseases such as late tumor and chronic hepatitis B.Slow releasing tablet of the present invention only need be taken medicine 2 times each 1 every day.Cutis Bufonis extract of the present invention gel skeleton type slow releasing tablet great advantage be that therapeutical effect is lasting, medicining times is few, toxic and side effects is low.Medicine can slowly discharge after entering gastrointestinal tract, and blood drug level " peak valley " fluctuation is little, can avoid surpassing the toxic and side effects for the treatment of blood drug level scope, can remain on again within the valid density scope (treatment window) to keep curative effect.Therefore, slow releasing tablet of the present invention not only can improve curative effect, reduces toxic and side effects, and can reduce medicining times, greatly improves the compliance that patient takes medicine, and is easy to use, need to be specially adapted to the chronic of Long-term taking medicine.
Adopt decoction and alcohol sedimentation technique to extract effective ingredient in the Cutis Bufonis among the present invention, technique is simple, and is with low cost, and its extract yield is 3.20~4.10%, the content of effective ingredient in the extract (cinobufotalin) is 1.50~2.00mg/g, can satisfy the demand of clinical treatment fully.
Hypromellose (HPMC) is as hydrophilic gel slow releasing tablet framework material,, odorless, tasteless cheap and easy to get because of it, fabulous stability and nonionic (its performance is not affected by pH) are arranged, be convenient to produce, both directly compressible also can pelletizing press sheet, and department is accepted by the countries in the world drug control.Therefore, first-selection of the present invention is selected hypromellose as the slow releasing tablet framework material.Adopt the slow releasing tablet of bioadhesive material carbomer and water-insoluble framework material ethyl cellulose preparation that preferably slow releasing function is also arranged, drug release pattern is identical as the slow releasing tablet of framework material with hypromellose.
Adopt mannitol, sorbitol, glucose as porogen among the present invention, be that at first they have good water solublity, can satisfy the requirement of dissolution of sustained-release tablets; Secondly this type of adjuvant hygroscopicity is very little, the granulation fast drying, and chemical stability is good, can reduce to a certain extent the strong hygroscopicity of Chinese medicine extract among the present invention; Again, it is a kind of sweeting agent of low in calories, low sugar, and heat absorption during because of dissolving, makes the oral cavity have refrigerant tasty and refreshing comfort, can cover to a certain extent the stench flavor of bitterness of Cutis Bufonis extract, has flavored action concurrently.
The present invention adopts ethanol or ethanol water to make wetting agent and granulates, the problems such as the difficulty of sieving that causes that purpose is to avoid aqueous binders to granulate, dry difficulty, easy puckery punching.
It is filler that the present invention adopts microcrystalline Cellulose, lactose and starch, and purpose is to improve the hygroscopicity of Cutis Bufonis extract, is beneficial to tabletting and carries out smoothly, guarantees preparation nonhygroscopic deliquescing between the storage life.
The distribution situation that the present invention adopts the method for respectively granulation can regulate principal agent and adjuvant, change the seriality of the gel barrier that forms behind framework material chance water or the Digestive system, need not add the release that other adjuvant just can be controlled slow releasing tablet to a certain extent thereby reach.
Slow releasing tablet drug release in early stage of the present invention is quick, can reach rapidly valid density, follows subsequently the dissolving of framework material, and medicine discharges gradually, keeps a stably drug release rate, thereby reaches the release request of slow releasing preparation.Simple, the easy row of this kind method, economic is fit to promote the use of, and has very strong practicality.
The present invention is according to 2005 editions two appendix XC dissolution methods of Chinese Pharmacopoeia the 3rd law regulation to the evaluation methodology of slow releasing tablet, adopt high performance liquid chromatography, effective ingredient (cinobufotalin) release in vitro situation is as the optimum prescription of index screening and preparation technology in the extract.Select 3 sampling time points from the tablets in vitro curve chart: first is 0.5~2 hour sampling time point of beginning, and whether be used for investigating medicine has prominent releasing; Second point is middle sampling time point, is used for determining drug release feature; Whether substantially complete last sampling time point is used for investigating release.Slow releasing tablet of the present invention is that 12h discharges slow releasing tablet, therefore investigated slow releasing tablet 2,6,10 hours Cumulative release amount.
Cutis Bufonis extract gel skeleton slow releasing tablet release in vitro curve-fitting results of the present invention shows, medicine by diffusion and (or) bulk erosion discharges, framework material finally can dissolve fully, drug release is complete, bioavailability is high.
Description of drawings
Fig. 1 is for adopting different model HPMC to prepare the external accumulative total of conventional slow releasing tablet release rate.
Fig. 2 is for adopting the variety classes filler to prepare the external accumulative total of conventional slow releasing tablet release rate.
Fig. 3 prepares the external accumulative total of conventional slow releasing tablet release rate for the filler that adopts different amounts.
Fig. 4 is the external accumulative total release rate of different method of granulating.
Fig. 5 is the external accumulative total release rate of different porogen.
Fig. 6 is the external accumulative total release rate with the porogen of consumption.
Fig. 7 is the external accumulative total release rate of different framework materials.
The specific embodiment
Below specific embodiment to being for making those skilled in the art understand better the present invention, but and be not used in the present invention done any restriction.
Embodiment 1
Different model hypromellose prescription 1,2,3 slow releasing tablet (conventional slow releasing tablet):
Take by weighing Cutis Bufonis extract extractum and framework material (HPMC K4M, K15M, three kinds of models of K100M), filler in selected prescription ratio, pulverized 60 mesh sieves behind the mix homogeneously.Spray into 95% ethanol water wet granulation, behind the particle drying, add moderate lubrication agent Pulvis Talci in the dried granule, mixing, tabletting, and get final product.The concrete prescription of R1, R2, R3 and release in vitro situation see Table 1, Fig. 1.The external Cumulative release amount of Cutis Bufonis extract slow releasing tablet of Fig. 1 presentation of results different model hypromellose preparation is variant.Wherein behind the R1 slow releasing tablet 6h in the extract effective ingredient (cinobufotalin) Cumulative release amount obviously increase, 10h cinobufotalin Cumulative release amount reaches 80%, but R2, R3 slow releasing tablet 10h cinobufotalin Cumulative release amount are lower than 30%.Illustrate when framework material HPMC K15M, HPMC K100M do the framework material of Cutis Bufonis extract extractum slow releasing tablet, the burst size of effective ingredient is excessively low in the 10h.Be that HPMC K4M is better as the gelatum skeleton material of this extract in the R1 prescription.
The prescription of 1 different model hypromellose (HPMC)
Embodiment 2
The method for making of prescription R7, the R8 of prescription R4, R5, the R6 of variety classes filler (microcrystalline Cellulose, lactose, starch) identical from the filler kind (microcrystalline Cellulose) consumption different (50%, 45%, 40%, 30%), R9, R10 slow releasing tablet is with embodiment 1.The concrete prescription of R4, R5, R6, R7, R8, R9, R10 sees Table 2.
Variety classes filler prescription R4, R5, R6 release in vitro situation are seen Fig. 2.Wherein be among the prescription R4, R5 slow releasing tablet 10h extract of filler effective ingredient (cinobufotalin) Cumulative release amount near 50% with microcrystalline Cellulose, lactose, the burst size that starch is done effective ingredient in the prescription R6 slow releasing tablet 10h of filler is excessively low.Fig. 2 presentation of results filler kind is different, and is influential to the external Cumulative release amount of slow releasing tablet, does the filler drug release with microcrystalline Cellulose, lactose very fast, and burst size is larger.
Different amounts filler prescription R7, R8, R9, R10 release in vitro situation are seen Fig. 3.As can be seen from the figure, prescription R7, the R8 of microcrystalline Cellulose consumption different (50%, 45%, 40%, 30%), R9, R10 slow releasing tablet 10h cinobufotalin Cumulative release amount be all greater than 50%, and increase the effective ingredient Cumulative release amount with the microcrystalline Cellulose consumption and increase.Fig. 3 presentation of results filler loading affects rate of release and the burst size of medicine.The large rate of release that can accelerate medicine of filler loading, but consumption is excessive, causes the framework material consumption to reduce, and slow release effect is bad.
The prescription of table 2 variety classes different amounts filler
Embodiment 3
Prescription 11,12 slow releasing tablet (different method of granulating) preparation process:
Total mixed granulation: with Cutis Bufonis extract extractum and all adjuvants crushing screening respectively, spray into an amount of concentration expressed in percentage by volume behind the mix homogeneously and be 95% ethanol water wet granule compression tablet, the gained slow releasing tablet is R11.
Method of the present invention: take by weighing Cutis Bufonis extract extractum powder and adjuvant in selected prescription ratio, pulverized respectively 60 mesh sieves.Described Cutis Bufonis extract extractum powder is divided into A part and B part, sprays into an amount of volumetric concentration behind A part and the described framework material mixing and be 85% ethanol water wet granulation, drying; Spray into an amount of ethanol wet granulation, drying behind B part and the filler mixing; To add moderate lubrication agent magnesium stearate behind two parts of granule mixings again, mixing, tabletting, namely obtaining Cutis Bufonis extract gel skeleton slow releasing tablet is R12.
The concrete prescription of R11 and R12 and release in vitro situation see Table 3, Fig. 4.External accumulative total releasing research result when Fig. 4 slow releasing tablet 2h and 6h shows, the Cumulative release amount of the R12 of method preparation of the present invention is significantly higher than total mixed granulation R11 slow releasing tablet, early stage, rate of release was faster than the R11 slow releasing tablet, external accumulative total during 6h discharges and reaches 50%, namely adopts the slow releasing tablet medicine of method preparation of the present invention in earlier stage to discharge better.Fig. 4 presentation of results adopts method of the present invention that Cutis Bufonis extract is divided into two parts, and respectively with mixing granulations such as framework material, filleies, the external accumulative total of the slow releasing tablet of acquisition discharges the slow releasing tablet that is better than always mixing the granulation preparation.
Table 3 method of granulating is investigated prescription
Embodiment 4
Take by weighing Cutis Bufonis extract extractum powder and adjuvant in selected prescription ratio, pulverized respectively 60 mesh sieves.Described Cutis Bufonis extract extractum powder is divided into A part and B part, and spraying into an amount of volumetric concentration behind A part and the described framework material mixing is the ethanol water wet granulation, drying; Spray into an amount of ethanol water wet granulation, drying behind the porogen of B part and filler and double taste masking (variety classes different amounts porogen as: sorbitol, mannitol, the glucose) mixing; To add moderate lubrication agent magnesium stearate behind two parts of granule mixings again, mixing, tabletting namely obtains Cutis Bufonis extract gel skeleton slow releasing tablet R13, R14, R15, R16 and variety classes different amounts filler R17, R18, R19 slow releasing tablet, and concrete prescription sees Table 4.R13, R14, R15, R16 release in vitro situation are seen Fig. 5.Fig. 5 presentation of results adds the porogen of the flavored action of holding concurrently in prescription, the external accumulative total release during slow releasing tablet Chinese medicine 6h about 50%, shows that the porogen of the flavored action of holding concurrently does not affect the drug release of slow releasing tablet substantially, and the effect of its effect and filler is similar.But the refrigerant interaction energy that its taste masking and suction produce obviously improves the stench flavor of Cutis Bufonis extract.
R17, R18, R19 release in vitro situation are seen Fig. 6.The consumption of Fig. 6 presentation of results porogen increases, external accumulative total during slow releasing tablet Chinese medicine 2h discharges significantly and increases, when consumption 5% and 10%, the external Cumulative release amount during 2h reaches 30%, shows that the consumption size of porogen affects drug releasing rate and the burst size that slow releasing tablet discharges early stage.
The prescription of table 4 variety classes different amounts porogen
Embodiment 5
Take by weighing Cutis Bufonis extract extractum powder and adjuvant in selected prescription ratio, pulverized respectively 60 mesh sieves.Described Cutis Bufonis extract extractum powder is divided into A part and B part, and spraying into an amount of volumetric concentration behind A part and the described framework material mixing is the ethanol water wet granulation, drying; Spray into an amount of ethanol water wet granulation, drying behind the porogen of B part and filler and double taste masking (variety classes different amounts porogen as: sorbitol, mannitol, the glucose) mixing; To add moderate lubrication agent magnesium stearate behind two parts of granule mixings again, mixing, tabletting namely obtains Cutis Bufonis extract gel skeleton slow releasing tablet R20, R21, R22 slow releasing tablet.The concrete prescription of R20, R21, R22 and release in vitro situation see Table 5, Fig. 7.Fig. 7 presentation of results all has slow releasing function with the Cutis Bufonis extract slow releasing tablet of framework material HPMC K4M, carbomer, ethyl cellulose preparation.HPMC K4M, carbomer have and meet water-soluble swollen, dissolution characteristics originally as hydrogel and bioadhesive material, the diffusion of the gel layer blocking medicine of formation after the dissolving, thus reach the purpose that delays drug release.Adopt in the present invention the Cutis Bufonis extract slow releasing tablet of water-insoluble framework material ethyl cellulose preparation also to present slow releasing function.The analysis reason may be that the recipe quantity of in the present invention Chinese medicine extract is larger, the thickness performance that this extract chance water presents is similar to the gel layer that forms after the gelatum skeleton material dissolving, stopped the release of medicine, and the hydrophobic performance of ethyl cellulose has slowed down the infiltration of moisture, therefore tablet presents slow release effect.
The prescription of the different framework materials of table 5
Embodiment 6
Cutis Bufonis extract extractum powder is to make with following method: it is raw material that dry maxima skin is cleaned post-drying, soak 30min, decoct 3 times, each 40min that decocts, the quality that at every turn adds water is 10 times of described raw materials quality, filter, merging filtrate is concentrated into 1/5 of original volume, add volumetric concentration and be 90% ethanol water and make that to contain amount of alcohol be 60%, 4 ℃ leave standstill 24h, filter, and filtrate is revolved and steamed to nothing alcohol flavor, add volumetric concentration and be 90% ethanol water and make that to contain amount of alcohol be 85%, 4 ℃ leave standstill 48h, filter, and filtrate revolving steamed to the thickness paste; 60 ℃ are dried to constant weight, pulverize.
Embodiment 7
Cutis Bufonis extract extractum powder is to make with following method: it is raw material that dry maxima skin is cleaned post-drying, soak 20min, decoct 4 times, each 30min that decocts, the quality that at every turn adds water is 8 times of described raw materials quality, filter, merging filtrate is concentrated into 1/6 of original volume, add volumetric concentration and be 90% ethanol water and make that to contain amount of alcohol be 60%, 4 ℃ leave standstill 28h, filter, and filtrate is revolved and steamed to nothing alcohol flavor, add volumetric concentration and be 90% ethanol water and make that to contain amount of alcohol be 85%, 4 ℃ leave standstill 44h, filter, and filtrate revolving steamed to the thickness paste; 60 ℃ are dried to constant weight, pulverize.
Embodiment 8
Cutis Bufonis extract extractum powder is to make with following method: it is raw material that dry maxima skin is cleaned post-drying, soak 40min, decoct 2 times, each 60min that decocts, the quality that at every turn adds water is 12 times of described raw materials quality, filter, merging filtrate is concentrated into 1/6 of original volume, add volumetric concentration and be 90% ethanol water and make that to contain amount of alcohol be 60%, 4 ℃ leave standstill 20h, filter, and filtrate is revolved and steamed to nothing alcohol flavor, add volumetric concentration and be 90% ethanol water and make that to contain amount of alcohol be 85%, 4 ℃ leave standstill 52h, filter, and filtrate revolving steamed to the thickness paste; 60 ℃ are dried to constant weight, pulverize.